Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL

M. Leiva, S. Moretti, H. Soilihi, I. Pallavicini, L. Peres, C. Mercurio, R. Dal Zuffo, S. Minucci, H. De Thé

Research output: Contribution to journalArticlepeer-review

Abstract

Aberrant histone acetylation was physiopathologically associated with the development of acute myeloid leukemias (AMLs). Reversal of histone deacetylation by histone deacetylase inhibitor (HDACis) activates a cell death program that allows tumor regression in mouse models of AMLs. We have used several models of PML-RARA-driven acute promyelocytic leukemias (APLs) to analyze the in vivo effects of valproic acid, a well-characterized HDACis. Valproic acid (VPA)-induced rapid tumor regression and sharply prolonged survival. However, discontinuation of treatment was associated to an immediate relapse. In vivo, as well as ex vivo, VPA-induced terminal granulocytic differentiation. Yet, despite full differentiation, leukemia-initiating cell (LIC) activity was actually enhanced by VPA treatment. In contrast to all-trans retinoic acid (ATRA) or arsenic, VPA did not degrade PML-RARA. However, in combination with ATRA, VPA synergized for PML-RARA degradation and LIC eradication in vivo. Our studies indicate that VPA triggers differentiation, but spares LIC activity, further uncouple differentiation from APL clearance and stress the importance of PML-RARA degradation in APL cure.

Original languageEnglish
Pages (from-to)1630-1637
Number of pages8
JournalLeukemia
Volume26
Issue number7
DOIs
Publication statusPublished - Jul 2012

Keywords

  • clonogenic activity
  • murine models
  • retinoic acid

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Fingerprint

Dive into the research topics of 'Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL'. Together they form a unique fingerprint.

Cite this